The study outcome measure was, to find out the relationship between the Drug interactions and polypharmacy and other factors such as age, gender, hospital stay. A prospective cross-sectional study was performed in general medicine department of tertiary care teaching hospital, Ongole, over a period 6 months. All the patients admitted to the general medicine department were included using appropriate criteria and analyzed for Drug–Drug Interactions (DDIs). These drug interactions in the study were analyzed using the Micromedex Drug Interactions. 905 cases were screened for DDIs, among them 45% of cases with more than 1DDIs. With a total of 848 interactions, aspirin + clopidogrel is the most common interaction pair and is reported by 10.81%, while atorvastatin + clopidogrel is the second most common interaction pair with 9.03% prevalence. 5% of the incidence of interaction was observed in the cases of 408 cases. The regression analysis results the significance level at 95% Confidence Interval (p≤0.05) of DDIs and polypharmacy. This study concludes that there is a significant association between prescription drugs and DDIs. This type of study helps improve the quality of life. Estimating the most common DDIs can assistance the medical practitioner to recommend the minimal risk prescriptions and the combination of drugs.